This invention relates to purine derivatives. More particularly, this invention relates to 9-(5-heteroaryltetrahydrofuranyl)purine derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.
These derivatives are selective, functional agonists of the human adenosine A2a receptor and may be used as anti-inflammatory agents in the treatment of, inter alia, diseases of the respiratory tract.
Adenosine is a ubiquitous molecule having a central role in mammalian intermediary metabolism. Independently, adenosine acts on multiple surface receptors to produce a variety of responses. Adenosine receptor classification has revealed the presence of at least four subtypes: A1, A2a, A2b and A3. Stimulation of adenosine A2 receptors on the surface of human neutrophils has been reported to potently inhibit a range of neutrophil functions. Activated neutrophils can damage lung tissue by release of reactive oxygen species, for example, superoxide anion radicals (O2xe2x88x92), and granule products, for example, human neutrophil elastase (HNE), amongst other inflammatory mediators. In addition, activated neutrophils perform both de novo synthesis and release of arachidonate products such as leukotriene B4 (LTB4). LTB4 is a potent chemo-attractant that recruits additional neutrophils to the inflammatory focus, whereas released O2xe2x88x92 and HNE adversely affect the pulmonary extracellular matrix. The A2 receptor subtype mediating many of these responses (O2xe2x88x92 and LTB4/HNE release and cell adhesion) is established as A2a. The A2 subtype (A2a or A2b) mediating the other effects remains to be established.
Selective agonist activity at the A2a receptor is considered to offer greater therapeutic benefit than the use of non-selective adenosine receptor agonists because interaction with other subtypes is associated with detrimental effects in the lung in animal models and human tissue studies. For example, asthmatics, but not non-asthmatics, bronchoconstrict when challenged with inhaled adenosine. This response is at least in part due to the activation of the A1 receptor subtype. Activation of A1 receptors also promotes neutrophil chemotaxis and adherence to endothelial cells, thus promoting lung injury. Furthermore, many patients with respiratory disease will be co-prescribed xcex22-agonists, and negative interaction has been shown in animal studies between isoprenaline and adenosine receptors negatively coupled to adenylate cyclase. Degranulation of human mast cells is promoted by activation of adenosine A2b receptors, thus selectivity over the A2b receptor is also advantageous.
We have now surprisingly found the present purine derivatives inhibit neutrophil function and are selective agonists of the adenosine A2a receptor. They may also have antagonist activity at the adenosine A3 receptor. The present compounds may be used to treat any disease for which an adenosine A2a receptor agonist is indicated. They can be used to treat a disease where leukocyte (e.g. neutrophil, eosinophil, basophil, lymphocyte, macrophage)-induced tissue damage is implicated. They are useful as anti-inflammatory agents in the treatment of diseases of the respiratory tract such as adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis. The present compounds may also be used in the treatment of septic shock, male erectile dysfunction, male factor infertility, female factor infertility, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori gastritis, non-Heliobacter pylori gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing.
Accordingly, the present invention provides a compound of the formula 
or a pharmaceutically acceptable salt or solvate thereof, wherein
R1 is (i) H, (ii) C1-C6 alkyl optionally substituted by 1 or 2 substituents each independently selected from fluorenyl, phenyl and naphthyl, said phenyl, naphthyl and fluorenyl being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo or cyano, or (iii) fluorenyl;
R2 is either
(a) xe2x80x94CH2NHSO2xe2x80x94Axe2x80x94R3 wherein
A is a bond or C1-C3 alkylene; and
R3 is (i) H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl or naphthyl, said C3-C8 cycloalkyl, phenyl and naphthyl being optionally substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R4R4Nxe2x80x94(C1-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, C2-C5 alkanoyl, halo, xe2x80x94OR4, cyano, xe2x80x94COOR4, C3-C8 cycloalkyl, xe2x80x94S(O)mR5, xe2x80x94NR4R4, xe2x80x94SO2NR4R4, xe2x80x94CONR4R4, xe2x80x94NR4COR5 or xe2x80x94NR4SO2R5, with the proviso that R3 is not H when A is a bond, or (ii) when A is C2-C3 alkylene, xe2x80x94NR8R9, xe2x80x94OR4, xe2x80x94COOR4, xe2x80x94OCOR5, xe2x80x94SO2R5, xe2x80x94CN, xe2x80x94SO2NR4R4, xe2x80x94NR4COR5 or xe2x80x94CONR4R4, or (iii) a C-linked, 4 to 11 membered, mono or bicyclic heterocycle having either from 1 to 4 ring nitrogen atom(s) or 1 or 2 nitrogen and 1 oxygen or 1 sulphur ring atoms, optionally C-substituted by oxo, C1-C6 alkoxy-(C1-C6)-alkyl, R6R6Nxe2x80x94(C1-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, fluoro-(C2-C5)-alkanoyl, halo, cyano, xe2x80x94OR6, R7, xe2x80x94COR6, xe2x80x94NR6R6, xe2x80x94COOR6, xe2x80x94S(O)mR7, xe2x80x94SO2NR6R6, xe2x80x94CONR6R6, xe2x80x94NR6SO2R7 or xe2x80x94NR6COR7 and optionally N-substituted by C1-C6 alkoxy-(C1-C6)-alkyl, R6R6Nxe2x80x94(C2-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C2-C5)-alkanoyl, R7, xe2x80x94COR6, xe2x80x94COOR6, xe2x80x94S(O)mR7, xe2x80x94SO2NR6R6 or xe2x80x94CONR6R6; or
(b) xe2x80x94CONR10xe2x80x94A1xe2x80x94R11 wherein
A1 is a bond or C1-C6 alkylene;
R10 is H or C1-C6 alkyl; and
R11 is (i) H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl or naphthyl, said C3-C8 cycloalkyl, phenyl and naphthyl being optionally substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R4R4Nxe2x80x94(C1-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, C2-C5 alkanoyl, halo, xe2x80x94OR4, cyano, xe2x80x94COOR4, C3-C8 cycloalkyl, xe2x80x94S(O)mR5, xe2x80x94NR4R4, xe2x80x94SO2NR4R4, xe2x80x94CONR4R4, xe2x80x94NR4COR5 or xe2x80x94NR4SO2R5, with the proviso that R11 is not H when A1 is a bond,
or (ii) when A1 is C2-C6 alkylene, xe2x80x94NR4R4, xe2x80x94OR4, xe2x80x94OCOR5, xe2x80x94SO2R5, xe2x80x94SO2NR4R4, xe2x80x94NR4SO2R5 or xe2x80x94NR4COR5,
or (iii) a C-linked, 4 to 11 membered, mono or bicyclic heterocycle having either from 1 to 4 ring nitrogen atom(s) or 1 or 2 nitrogen and 1 oxygen or 1 sulphur ring atoms, optionally C-substituted by oxo, C1-C6 alkoxy-(C1-C6)-alkyl, R6R6Nxe2x80x94(C1-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, fluoro-(C2-C5)-alkanoyl, halo, cyano, xe2x80x94OR6, R7, xe2x80x94COR6, xe2x80x94NR6R6, xe2x80x94COOR6, xe2x80x94S(O)mR7, xe2x80x94SO2NR6R6, xe2x80x94CONR6R6, xe2x80x94NR6SO2R7 or xe2x80x94NR6COR7 and optionally N-substituted by C1-C6 alkoxy-(C1-C6)-alkyl, R6R6Nxe2x80x94(C2-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C2-C5)-alkanoyl, R7, xe2x80x94COR6, xe2x80x94COOR7, xe2x80x94SO2R7, xe2x80x94SO2NR6R6 or xe2x80x94CONR6R6,
or (iv) when A1 is C2-C6 alkylene, N-linked azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, homopiperidinyl or tetrahydroquinolinyl, each being optionally C-substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R4R4Nxe2x80x94(C1-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, C2-C5 alkanoyl, halo, xe2x80x94OR4, cyano, xe2x80x94COOR4, C3-C8 cycloalkyl, xe2x80x94S(O)mR5, xe2x80x94NR4R4, xe2x80x94SO2NR4R4, xe2x80x94CONR4R4, xe2x80x94NR4COR5 or xe2x80x94NR4SO2R5 and said piperazinyl and homopiperazinyl being optionally substituted on the nitrogen not attached to A1by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C2-C6)-alkyl, R4R4Nxe2x80x94(C2-C6)-alkyl, halo-(C1-C6)-alkyl, C2-C5 alkanoyl, xe2x80x94COOR5, C3-C8 cycloalkyl, xe2x80x94SO2R5, xe2x80x94SO2NR4R4 or xe2x80x94CONR4R4,
or (v) when A1is C1-C6 alkylene, xe2x80x94COOR4, xe2x80x94CN or xe2x80x94CONR4R4; or
(c) xe2x80x94Xxe2x80x94NR12axe2x80x94Yxe2x80x94NR13R14 wherein
X is xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94; and
R12a is H or C1-C6 alkyl; or
(d) xe2x80x94COxe2x80x94NR18xe2x80x94X1xe2x80x94NR12xe2x80x94Yxe2x80x94NR13R14 wherein
(i) X1 is (1) unbranched C2-C3 alkylene optionally substituted by C1-C6 alkyl or C3-C8 cycloalkyl or (2) a group of the formula xe2x80x94(CH2)nxe2x80x94Wxe2x80x94(CH2)pxe2x80x94 wherein W is C5-C7 cycloalkylene, n is 0 or 1 and p is 0 or 1;
R18 is H or C1-C6 alkyl; and
R12 is H or C1-C6 alkyl; or
(ii) X1 and R12, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl; and
R18 is H or C1-C6 alkyl; or
(iii) X1 and R18, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl; and
R12 is H or C1-C6 alkyl;
Y is CO, CS, SO2 or Cxe2x95x90N(CN);
R4 is H, C1-C6 alkyl, C3-C8 cycloalkyl or phenyl;
R5 is C1-C6 alkyl, C3-C8 cycloalkyl or phenyl;
R6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, naphthyl or het;
R7 is C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, naphthyl or het;
either, R8 and R9, taken together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperidinyl, homopiperazinyl or tetrahydroisoquinolinyl, each being optionally substituted on a ring carbon atom by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R4R4Nxe2x80x94(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, xe2x80x94CONR4R4, xe2x80x94COOR4 or C2-C5 alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro-(C1-C6)-alkoxy, halo, xe2x80x94OR4, cyano, xe2x80x94S(O)mR5, xe2x80x94NR4R4, xe2x80x94SO2NR4R4, xe2x80x94NR4COR5 or xe2x80x94NR4SO2R5, and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to A or the C2-C6 alkylene group, as the case may be, by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C2-C6)-alkyl, R4R4Nxe2x80x94(C2-C6)-alkyl, fluoro-(C1-C6)-alkyl, C2-C5 alkanoyl, xe2x80x94COOR5, C3-C8 cycloalkyl, xe2x80x94SO2R5, xe2x80x94SO2NR4R4 or xe2x80x94CONR4R4, or, R8 is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl or benzyl and R9 is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl, fluoro-(C1-C6)-alkyl, xe2x80x94CONR4R4, xe2x80x94COOR5, xe2x80x94COR5, xe2x80x94SO2R5 or xe2x80x94SO2NR4R4, said C1-C6 alkyl being optionally substituted by phenyl;
either, R13 and R14, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each being optionally substituted on a ring nitrogen or carbon atom by C1-C6 alkyl or C3-C8 cycloalkyl and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by xe2x80x94NR15R16 or xe2x80x94OR4,
or, R13 is H, C1-C6 alkyl, C3-C8 cycloalkyl or benzyl, said C1-C6 alkyl being optionally substituted by C3-C8 cycloalkyl, and R14 is
(1) azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or het1, or
(2) xe2x80x94(C2-C6 alkylene)-NR8R9, or
(3) xe2x80x94(C1-C6 alkylene)-R17, or
(4) C1-C6 alkyl or C3-C8 cycloalkyl;
R15 and R16 are either each independently H or C1-C6 alkyl or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by C1-C6 alkyl;
R17 is (i) phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94(C1-C3 alkylene)-(C1-C6 alkoxy), halo, cyano, xe2x80x94(C1-C3 alkylene)-CN, xe2x80x94CO2H, xe2x80x94(C1-C3 alkylene)-CO2H, xe2x80x94CO2(C1-C6 alkyl), xe2x80x94(C1-C3 alkylene)-CO2(C1-C6 alkyl), xe2x80x94(C1-C3 alkylene)-NR24R24, xe2x80x94CONR24R24 or xe2x80x94(C1-C3 alkylene)-CONR24R24, or
(ii) azetidin-2-yl, azetidin-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-2-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or het1;
m is 0, 1 or 2;
het, used in the definitions of R6 and R7, means C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, each optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, cyano or halo;
het1, used in the definition of R14 and R17, is a C-linked, 4- to 6-membered ring heterocycle having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulphur ring heteroatom, optionally substituted by C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, hydroxy, oxo or halo;
R19 is a C-linked, 5-membered aromatic heterocycle containing either (i) from 1 to 4 ring nitrogen atoms or (ii) 1 or 2 ring nitrogen atoms and 1 oxygen or 1 sulphur ring atom, said heterocycle being optionally substituted by C1-C6 alkyl, said C1-C6 alkyl being optionally substituted by phenyl, xe2x80x94OH, C1-C6 alkoxy or xe2x80x94NR20R21;
R20 and R21 are either each independently H or C1-C6 alkyl or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by C1-C6 alkyl; and
R24 is H or C1-C6 alkyl optionally substituted by cyclopropyl. In the above definitions, halo means fluoro, chloro, bromo or iodo and alkyl, alkylene, alkanoyl and alkoxy groups containing the requisite number of carbon atoms can be unbranched or branched chain. The heterocycle, as defined in R2, parts (a)(iii) and (b)(iii), above may be aromatic or fully or partially saturated. The expressions xe2x80x98C-linkedxe2x80x99 and xe2x80x98N-linkedxe2x80x99 used in the definition of R2, het and het1 mean that the group is linked to the adjacent atom by a ring carbon or nitrogen atom, respectively. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples of alkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene and 1,2-propylene. Examples of alkanoyl include acetyl and propanoyl. Examples of cycloalkylene include cyclopentylene, cyclohexylene and cycloheptalyene. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of cycloalkoxy include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy. Examples of het1 include pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl.
The pharmaceutically acceptable salts of the compounds of the formula (i) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate, pamoate, adipate and xinafoate (1-hydroxy-2-naphthoate) salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.
For a review on suitable salts see Berge et al, J. Pharm. Sci., 1977, 66, 1-19.
The pharmaceutically acceptable solvates of the compounds of the formula (I) and salts thereof include the hydrates thereof.
Also included within the present scope of the compounds of the formula (I) and salts thereof are polymorphs and radiolabelled derivatives thereof.
A compound of the formula (I) may contain one or more additional asymmetric carbon atoms and therefore exist in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds of the formula (I) and, where appropriate, the individual tautomers thereof, together with mixtures thereof.
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
Preferably, R1 is C1-C6 alkyl optionally substituted by 1 or 2 substituents each independently selected from fluorenyl, phenyl and naphthyl, said phenyl, naphthyl and fluorenyl being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo or cyano.
Preferably, R1 is C1-C6 alkyl substituted by 1 or 2 phenyl groups, said phenyl, groups being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo or cyano.
Preferably, R1 is C1-C6 alkyl substituted by 1 or 2 phenyl groups.
Preferably, R1 is C1-C4 alkyl substituted by 1 or 2 phenyl groups.
Preferably, R1 is C1-C2 alkyl substituted by 1 or 2 phenyl groups.
Preferably, R1 is diphenylethyl.
Preferably, R1 is 2,2-diphenylethyl.
Preferably, R2 is xe2x80x94CH2NHSO2xe2x80x94Axe2x80x94R3, xe2x80x94CONR10xe2x80x94A1xe2x80x94R11 or xe2x80x94Xxe2x80x94NR12axe2x80x94Yxe2x80x94NR13R14.
Preferably, R2 is xe2x80x94CH2NHSO2CH2CH(CH3)2, xe2x80x94CONHCH2CH2Ph, xe2x80x94CH2NHCONHCH2CH2N[CH(CH3)2][cyclopentyl], xe2x80x94CH2NHCONHCH2CH2(piperidin-1-yl) or xe2x80x94CONHCH2CH2(piperidin-1-yl).
Preferably, R2 is xe2x80x94CH2NHSO2CH2CH(CH3)2, xe2x80x94CH2NHCONHCH2CH2N[CH(CH3)2][cyclopentyl], or xe2x80x94CH2NHCONHCH2CH2(piperidin-1-yl).
Preferably, R19 is C-linked tetrazolyl, oxadiazolyl, oxazolyl or triazolyl each optionally substituted by C1-C6 alkyl, said C1-C6 alkyl being optionally substituted by phenyl, xe2x80x94OH, C1-C6 alkoxy or xe2x80x94NR20R21.
Preferably, R19 is C-linked tetrazolyl, oxadiazolyl, oxazolyl or triazolyl each optionally substituted by C1-C6 alkyl.
Preferably, R19 is 1,2,3,4-tetrazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2-oxazol-5-yl, 1,2,4-triazol-3-yl or 1,2,3-triazol-4-yl each optionally substituted by C1-C6 alkyl.
Preferably, R19 is 1,2,3,4-tetrazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2-oxazol-5-yl, 1,2,4-triazol-3-yl or 1,2,3-triazol-4-yl each optionally substituted by ethyl.
Preferably, R19 is 2-ethyl-1,2,3,4-tetrazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl, 5-ethyl-1,2,4-oxadiazol-3-yl, 3-ethyl-1,2-oxazol-5-yl, 1-ethyl-1,2,4-triazol-3-yl or 1-ethyl-1,2,3-triazol-4-yl.
Preferably, R19 is 3-ethyl-1,2,3,4-tetrazol-5-yl or 1-ethyl-1,2,3-triazol-4-yl.
Preferably, A is a bond, methylene or 1,2-propylene.
Preferably, R3 is C1-C6 alkyl.
Preferably, R3 is C1-C4 alkyl.
Preferably, R3 is methyl, propyl or butyl.
Preferably, R3 is methyl, prop-2-yl or 2-methylprop-1-yl.
Preferably, xe2x80x94Axe2x80x94R3 is C1-C6 alkyl.
Preferably, xe2x80x94Axe2x80x94R3 is C1-C4 alkyl.
Preferably, xe2x80x94Axe2x80x94R3 is butyl.
Preferably, xe2x80x94Axe2x80x94R3 is 2-methylprop-1-yl.
Preferably, R10 is H.
Preferably, A1 is C1-C6 alkylene.
Preferably, A1 is C2-C6 alkylene.
Preferably, A1 is C1-C4 alkylene.
Preferably, A1 is C2-C4 alkylene.
Preferably, A1 is C1-C2 alkylene.
Preferably, A1 is ethylene.
Preferably, A1 is 1,2-ethylene.
Preferably, R11 is (i) phenyl optionally substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R4R4Nxe2x80x94(C1-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, C2-C5 alkanoyl, halo, xe2x80x94OR4, cyano, xe2x80x94COOR4, C3-C8 cycloalkyl, xe2x80x94S(O)mR5, xe2x80x94NR4R4, xe2x80x94SO2NR4R4, xe2x80x94CONR4R4, xe2x80x94NR4COR5 or xe2x80x94NR4SO2R5 or (ii) piperidin-1-yl optionally C-substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R4R4Nxe2x80x94(C1-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, C2-C5 alkanoyl, halo, xe2x80x94OR4, cyano, xe2x80x94COOR4, C3-C8 cycloalkyl, xe2x80x94S(O)mR5, xe2x80x94NR4R4, xe2x80x94SO2NR4R4, xe2x80x94CONR4R4, xe2x80x94NR4COR5 or xe2x80x94NR4SO2R5.
Preferably, R11 is phenyl or piperidin-1-yl.
Preferably, X is xe2x80x94CH2xe2x80x94.
Preferably, R12a is H.
Preferably, Y is CO.
Preferably, R13 is H.
Preferably, R14 is xe2x80x94(C2-C6 alkylene)-NR8R9.
Preferably, R14 is xe2x80x94(C2-C4 alkylene)-NR8R9.
Preferably, R14 is -(ethylene)-NR8R9.
Preferably, R14 is xe2x80x94CH2CH2NR8R9.
Preferably, either (i) R8 and R9, taken together with the nitrogen atom to which they are attached, represent piperidinyl, said piperidinyl being optionally substituted on a ring carbon atom by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R4R4Nxe2x80x94(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, xe2x80x94CONR4R4, xe2x80x94COOR4 or C2-C5 alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro-(Cl-C6)-alkoxy, halo, xe2x80x94OR4, cyano, xe2x80x94S(O)mR5, xe2x80x94NR4R4, xe2x80x94SO2NR4R4, xe2x80x94NR4COR5 or (ii) R8 is C1-C6 alkyl and R9 is C3-C8 cycloalkyl.
Preferably, either R8 and R9, taken together with the nitrogen atom to which they are attached, represent piperidinyl, or R8 is C1-C3 alkyl and R9 is C3-C5 cycloalkyl.
Preferably, either R8 and R9, taken together with the nitrogen atom to which they are attached, represent piperidinyl, or R8 is propyl and R9 is cyclopentyl.
Preferably, either R8 and R9, taken together with the nitrogen atom to which they are attached, represent piperidinyl, or R8 is prop-2-yl and R9 is cyclopentyl.
Preferred examples of compounds of the formula (I) include those of the Examples section hereafter, especially Examples 9, 10 and 11, and the pharmaceutically acceptable salts and solvates thereof.
The compounds of the formula (I) can be prepared by conventional routes such as by the procedures described in the general methods presented below or by the specific methods described in the Examples section, or by similar methods thereto. The present invention also encompasses these processes for preparing the compounds of formula (I), in addition to any novel intermediates used therein. In the general methods described, R1, R2 and R19 are as previously defined unless otherwise stated.
1. All the compounds of formula (I) may be prepared by the deprotection of a compound of formula 
wherein P1 and P2 represent suitable protecting groups which may be the same or different or P1 and P2, when taken together, represent a suitable protecting group. Examples of suitable protecting groups will be apparent to the skilled person [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. Preferred individual protecting groups are silyl (substituted with three groups independently selected from aryl and alkyl), alkanoyl and aroyl. A preferred protecting group where P1 and P2 form part of the same protecting group is where P1 and P2 taken together are C1-C6 alkylene. Particularly preferred individual protecting groups are acetyl and benzoyl. A particularly preferred protecting group where P1 and P2 form part of the same protecting group is where P1 and P2 taken together are 1,1-dimethylmethylene. Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P1 an P2 are each acetyl, the protecting groups may be removed by treating a solution of the compound of formula (II) in a suitable solvent, such as a mixture of water and methanol, with a base such as sodium carbonate, typically at room temperature.
The protecting groups P1 and P2 may be removed together in a single step or sequentially, in either order.
Compounds of the formula (II) may be prepared by the reaction of a derivatised form of a compound of the formula 
with a compound of the formula 
wherein W1 is methyl or phenyl and P1 and P2 are as defined above. In a typical procedure, the compound of the formula (III) is heated with N,O-bis(trimethylacetamide) in an inert solvent such as 1,1,1-trichloroethane, the solvent is removed and a solution of the residue, in a suitable solvent such as toluene, is heated, preferably under reflux, with the compound of the formula (IV) and trimethylsilyltriflate.
Compounds of the formula (III) may be prepared by the deprotection of a compound of the formula 
in which P3 is a suitable protecting group. Examples of suitable protecting groups will be apparent to the skilled person [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. A preferred protecting group is that in which P3 represents tetrahydropyran-2-yl. Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P3 is tetrahydropyran-2-yl, the protecting group may be removed by treating a solution of the compound of the formula (V) in a suitable solvent, such as ethanol, with an acid such as hydrochloric acid.
Compounds of the formula (V) may be prepared by the routes shown in Schemes 1 to 5 in which Lx is a suitable leaving group, preferably chloro, A2 is an activating group, as defined below, P3 is a suitable protecting group, as defined above, and E is C1-C6 alkyl. 
As shown in Scheme 1, compounds of the formula (V) in which R2 is xe2x80x94CH2NHSO2xe2x80x94Axe2x80x94R3 may be prepared by the reaction of a compound of the formula (VI) with a compound of the formula (VII). In a typical procedure, a solution of the compound of the formula (VI) in a suitable inert solvent such as dichloromethane is treated with the compound of the formula (VII). An acid acceptor such as triethylamine may optionally be added. Compounds of the formula (VI) may be prepared by the reduction of a compound of the formula (VIII). The reduction may be carried out with any suitable hydride reducing agent or by hydrogenation. In a typical procedure, a solution of the compound of the formula (VIII) in a suitable solvent such as ethanol is saturated with ammonia gas, treated with an appropriate hydrogenation catalyst such as Pearlman""s catalyst and pressurised with hydrogen, preferably to about 414 kPa (60 psi). Compounds of the formula (VIII) may be prepared by reacting a compound of the formula (IX) with a source of cyanide anion such as potassium cyanide. The reaction is typically carried out in a solvent such as N,N-dimethylformamide at an elevated temperature. Compounds of the formula (IX) may be prepared by the oxidation of a compound of the formula (X). In a typical procedure, an aqueous solution of potassium peroxymonosulphate is added to a solution of the compound of the formula (X) and sodium hydrogencarbonate in a suitable solvent, such as a mixture of water and acetone. Compounds of the formula (X) may be prepared by the displacement of chloride in a compound of the formula (XI) with thiomethoxide. Typically, the reaction is carried out in a polar solvent such as N,N-dimethylformamide, at elevated temperatures and under an atmosphere of nitrogen. Thiomethoxide is used as an alkali metal salt such as sodium thiomethoxide. Compounds of the formula (XI) may be prepared by the reaction of a compound of the formula (XII) with a compound of the formula (XIV). Typically, a solution of the dichloropurine (XII) in a suitable solvent such as isopropyl alcohol is treated with the compound of the formula (XIV) and heated under reflux. An additional acid acceptor such as N,N-diphenyl-N-ethylamine may optionally be added. Compound (XII) may be prepared by the protection of 2,6-dichloro-9H-purine (XIII). Suitable conditions for the protection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P3 is tetrahydropyran-2-yl, a solution of 2,6-dichloro-9H-purine (XIII) in a suitable solvent such as ethyl acetate is treated with dihydropyran and an acid catalyst such as 4-toluenesulphonic acid, usually at an elevated temperature. 
As shown in Scheme 2, compounds of the formula (V) in which R2 is xe2x80x94CONR10xe2x80x94A1xe2x80x94R11 may be prepared by the reaction of a compound of the formula (XV) with a compound of the formula (XVII), preferably at an elevated temperature, most preferably at from 100 to 150xc2x0 C. In a typical procedure, the compound of the formula (XV) and the compound of the formula (XVII) are heated together at 130xc2x0 C. Compounds of the formula (XV) may be prepared by the sequential alcoholysis and hydrolysis of a compound of the formula (VIII). In a typical procedure, a solution of the compound of the formula (VIII) in an alcoholic solvent EOH (wherein E is as defined above) is treated with the sodium alkoxide of the formula EONa (wherein E is as defined above) and heated under reflux. The resulting mixture is cooled and evaporated and the resulting residue is dissolved in a suitable solvent such as a mixture of tetrahydrofuran and water (e.g. a 3:1 mixture thereof) and treated with an acid such as acetic acid. The resulting mixture is heated at an elevated temperature, preferably under reflux, to give the compound of the formula (XV). 
As shown in Scheme 3, compounds of the formula (V) in which R2 is xe2x80x94CH2xe2x80x94NR12axe2x80x94Yxe2x80x94NR13R14 may be prepared the reaction of a compound of the formula (XVIII) with an appropriate reagent, as described below.
Compounds of the formula (V) in which R2 is xe2x80x94CH2xe2x80x94NR12axe2x80x94COxe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula 
in which L1 is a suitable leaving group, with a compound of the formula (XVIII) in a suitable solvent, such as a mixture of toluene and isopropanol, optionally at an elevated temperature, e.g. under reflux. The leaving group L1 is preferably halo (e.g. chloro) or imidazol-1-yl, most preferably imidazol-1-yl. Compounds of the formula (XIX) wherein L1 is imidazol-1-yl may be prepared by the reaction of a compound of the formula
R13R14NHxe2x80x83xe2x80x83(XX)
with 1,1xe2x80x2-carbonyldiimidazole. In a typical reaction a compound of the formula (XX) is added to a solution of 1,1xe2x80x2-carbonyldiimidazole in a suitable solvent such as dichloromethane. Compounds of the formula (XX) are either commercially available or may be prepared by standard techniques well known to persons skilled in the art.
Compounds of the formula (V) in which R2 is xe2x80x94CH2xe2x80x94NR12axe2x80x94CSxe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula
L2L3Cxe2x95x90Sxe2x80x83xe2x80x83(XXI)
in which L2 and L3 are suitable leaving groups, with a compound of the formula (XVIII) followed by the addition of a compound of the formula (XX). The leaving groups L2 and L3 may be the same or different and are typically each either xe2x80x94S(C1-C6 alkyl) or imidazol-1-yl. Preferably, L2 and L3 are each methylthio or imidazol-1-yl. In a typical procedure, a solution of the compound of the formula (XVIII) in a suitable solvent, such as ethanol, is treated with the compound of the formula (XXI), preferably at an elevated temperature, most preferably under reflux. When analysis by thin layer chromatography shows that a substantially complete reaction has occurred, a compound of the formula (XX) is added and the reaction mixture is preferably heated, most preferably under reflux
Compounds of the formula (V) in which R2 is xe2x80x94CH2xe2x80x94NR12axe2x80x94SO2xe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula
R13R14NSO2L4xe2x80x83xe2x80x83(XXII)
in which L4 is a suitable leaving group, typically halo, with a compound of the formula (XVIII), optionally in the presence of an acid acceptor. Preferably, L4 is chloro. In a typical example, a solution of the compound of the formula (XVIII) in a suitable solvent, such as pyridine, is treated with the compound of the formula (XXII) and preferably heated, most preferably at about 90xc2x0 C. Compounds of the formula (XXII) may be prepared by treating a compound of the formula
R13R14NSO3Hxe2x80x83xe2x80x83(XXIII)
with an activating agent. In a typical example, where L4 is chloro, a solution of a compound of the formula (XXIII), in a suitable solvent such as toluene, is treated with PCl5 and heated, preferably under reflux. Compounds of the formula (XXIII) may be prepared by treating a compound of the formula (XX) with chlorosulphonic acid. In a typical procedure, a solution of the compound of the formula (XX) in a suitable solvent, such as dichloromethane, is treated with chlorosulphonic acid, optionally in the presence of a proton acceptor such as triethylamine.
Compounds of the formula (V) in which R2 is xe2x80x94CH2xe2x80x94NR12axe2x80x94Cxe2x95x90N(CN)xe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula
L5L6Cxe2x95x90N(CN)xe2x80x83xe2x80x83(XXIV)
in which L5 and L6 are suitable leaving groups, with a compound of the formula (XVIII), followed by the addition of a compound of the formula (XX). The leaving groups L5 and L6 may be the same or different and are typically each selected from halo and xe2x80x94S(C1-C6 alkyl). Preferably, L5 and L6 are each methythio. In a typical procedure, where L5 and L6 are each methylthio, a solution of the compound of the formula (XVIII) in a suitable solvent, such as ethanol, is treated with dimethylcyanothioimidocarbamate, preferably at room temperature. When a substantially complete reaction is indicated by thin layer chromatography (TLC), a compound of the formula (XX) is added and the reaction mixture is preferably heated, most preferably under reflux.
Compounds of the formula (XVIII) may be prepared by the reduction of a compound of the formula (VIII) with a suitable reducing agent, preferably a palladium catalyst and hydrogen gas, in the presence of a compound of the formula
R12aNH2xe2x80x83xe2x80x83(XXV).
In a typical procedure, where R12a is H, a compound of the formula (VIII) is dissolved in a suitable solvent, such as ethanol, which has been saturated with ammonia gas, a palladium catalyst such as 10% w/w palladium on carbon is added and the reaction mixture is stirred under an atmosphere of hydrogen gas, typically at a pressure of 414 kPa (60 psi). Compounds of the formula (XXV) are either commercially available or easily prepared by methods well known in the art. 
As shown in Scheme 4, compounds of the formula (V) in which R2 is xe2x80x94CH2CH2xe2x80x94NR12axe2x80x94Yxe2x80x94NR13R14 may be prepared the reaction of a compound of the formula (XXVI) with an appropriate reagent. The methods and reagents used are the same as those used to prepare compounds of the formula (V) from a compound of the formula (XVIII). Compounds of the formula (XXVI) may be prepared by the reduction of a compound of the formula (XXVII) with a suitable reducing agent in the presence of a compound of the formula (XXV). A preferred reducing agent is Raney nickel, optionally in the presence of hydrogen gas. In a typical procedure, where R12a is H, the compound of the formula (XXVII) is dissolved in a suitable solvent, such as ethanol, which has been saturated with ammonia gas, Raney nickel is added and the reaction mixture is shaken, preferably at room temperature. Compounds of the formula (XXVII) may be prepared by the displacement of a leaving group xe2x80x98OA2xe2x80x99, in which A2 is an activating group, from a compound of the formula (XXVIII) with cyanide anion. In a typical example, a solution of the compound of the formula (XXVIII) in a suitable solvent, such as N,N-dimethylformamide, is treated with a source of cyanide ion, such as potassium cyanide to give the compound of the formula (XXVII). Examples of suitable choices for A2 will be apparent to the skilled man [see for example xe2x80x98Advanced Organic Chemistry (Third Edition)xe2x80x99, Jerry March, Wiley-Interscience, 1985]. Preferably, A2 is (C1-C6)alkylsulphonyl, phenylsulphonyl or (C1-C6)alkylphenylsulphonyl. Most preferably, A2 is methylsulphonyl. Compounds of the formula (XXVIII) may be prepared by the activation of the free hydroxyl in a compound of the formula (XXIX). In a typical procedure, where A2 is methylsulphonyl, a solution of the compound of the formula (XXIX) in a suitable solvent, such as dichloromethane, is treated with methanesulphonyl chloride in the presence of a proton acceptor such as triethylamine. Compounds of the formula (XXIX) may be prepared by the reduction of an ester of the formula (XV) with a suitable reducing agent, such as lithium borohydride, in a suitable solvent, such as tetrahydrofuran. 
As shown in Scheme 5, compounds of the formula (V) in which R2 is xe2x80x94COxe2x80x94NR18xe2x80x94X1xe2x80x94NR12xe2x80x94Yxe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula (XV) with a compound of the formula (XXX), optionally at an elevated temperature, optionally in an inert solvent such as 1,2-dimethoxyethane or 2-methoxyethyl ether and optionally under pressure. Preferably the reaction is carried out in the absence of solvent at a temperature of from 100-120xc2x0 C. Compounds of the formula (XXX) may be prepared by the reaction of a compound of the formula (XXXI) with an appropriate reagent and under suitable conditions in the same way that a compound of the formula (V) may be prepared from a compound of the formula (XVIII). The skilled person will appreciate that in order to achieve the desired degree of regioselectivity, a suitable protecting group (e.g. trifluoroacetyl) may optionally be used for this reaction located on a chosen N atom of a compound of the formula (XXXI). Compounds of the formula (XXXI) may be prepared by conventional procedures.
2. Compounds of the formula (I) in which in which R2 is xe2x80x94CH2NHSO2xe2x80x94Axe2x80x94R3 may be prepared by the reaction of a compound of the formula 
with a compound of the formula (VII) in which Lx is as defined above. In a typical procedure, a solution of the compound of the formula (XXXII) in a suitable inert solvent such as dichloromethane is treated with the compound of the formula (VII). An acid acceptor such as triethylamine may optionally be added.
Compounds of the formula (XXXII) may be prepared by the route shown in Scheme 6 in which P1 and P2 are as defined above. 
In Scheme 6, compounds of the formula (XXXII) may be prepared by the deprotection of a compound of the formula (XXXIIA). Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P1 and P2 are each acetyl, the protecting groups may be removed by treating a solution of the compound of formula (XXXIIA) in a suitable solvent, such as a mixture of water and methanol, with a base such as sodium carbonate, typically at room temperature. Compounds of the formula (XXXIIA) may be prepared by the reduction of a compound of the formula (XXXIII). The reduction may be carried out with any suitable hydride reducing agent or by hydrogenation. In a typical procedure, a solution of the compound of the formula (XXXIII) in a suitable solvent such as ethanol is saturated with ammonia gas, treated with an appropriate hydrogenation catalyst such as Pearlman""s catalyst and pressurised with hydrogen, preferably to about 414 kPa (60 psi). In certain cases, protecting groups P1 and P2 will be removed by the conditions employed in the reduction of a compound of the formula (XXXIII) and a compound of the formula (XXXII) will be obtained directly. Compounds of the formula (XXXIII) may be prepared by the reaction of a derivatised form of a compound of the formula (XXXIV) with a compound of the formula (IV), in which W1 is as defined above. In a typical procedure, the compound of the formula (XXXIV) is heated with N,O-bis(trimethylacetamide) in an inert solvent such as 1,1,1-trichloroethane, the solvent is removed and a solution of the residue, in a suitable solvent such as toluene, is heated, preferably under reflux, with the compound of the formula (IV) and trimethylsilyltriflate. Compounds of the formula (XXXIV) may be prepared by the deprotection of a compound of the formula (VIII), in which P3 is as defined above. Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P3 is tetrahydropyran-2-yl, the protecting group may be removed by treating a solution of the compound of the formula (VIII) in a suitable solvent, such as ethanol, with an acid such as hydrochloric acid.
3. Compounds of the formula (I) in which in which R2 is xe2x80x94CH2xe2x80x94NR12axe2x80x94Yxe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula 
with an appropriate reagent and under appropriate conditions in the same way that a compound of the formula (V) may be prepared from a compound of the formula (XVIII). It will be appreciated by the skilled man that in the case where Y is xe2x80x94CSxe2x80x94 or xe2x80x94Cxe2x95x90N(CN)xe2x80x94, the final intermediates will be compounds of the formula (XXXVI) and (XXXVII), respectively, in which L7 represents either of L2 or L3 and L8 represents either of L5 or L6. 
Compounds of the formula (XXXV) may be prepared by the reduction of a compound of the formula (XXXIII) with a suitable reducing agent, preferably a palladium catalyst and hydrogen gas, in the presence of a compound of the formula (XXV), and subsequent deprotection of the product so obtained in cases where the protecting groups P1 and P2 are not removed by the conditions employed for the reduction. In a typical procedure, where R12a is H, a compound of the formula (XXXIII) is dissolved in a suitable solvent, such as ethanol, which has been saturated with ammonia gas, a palladium catalyst such as 10% w/w palladium on carbon is added and the reaction mixture is stirred under an atmosphere of hydrogen gas, typically at a pressure of 414 kPa (60 psi).
4. Compounds of the formula (I) in which R2 is xe2x80x94CH2xe2x80x94NR12axe2x80x94COxe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula (XXXV) with a compound of the formula
L9COL10xe2x80x83xe2x80x83(XXXVIII)
in which L9 and L10 are suitable leaving groups to form an intermediate of the formula 
in which L11 represents either of the leaving groups L9 or L10 and the subsequent reaction of this intermediate with a compound of the formula (XX). Preferably, L9 and L10 are each either halo or imidazol-1-yl. Most preferably L9 and L10 are each imidazol-1-yl. In a typical example, where L9 and L10 are each imidazol-1-yl, a solution of the compound of the formula (XXXV) in a suitable solvent, such as dichloromethane, is treated with 1,1xe2x80x2-carbonyldiimidazole. The reaction mixture is stirred, preferably at room temperature, until thin layer chromatography (TLC) indicates that a substantially complete reaction has occurred and then a compound of the formula (XX) is added to give the compound of the formula (I).
5. Compounds of the formula (I) in which R2 is xe2x80x94CH2xe2x80x94NR12axe2x80x94CSxe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula (XXXV) with a compound of the formula
R14R13Nxe2x80x94CSxe2x80x94L12xe2x80x83xe2x80x83(XXXX)
in which L12 is a suitable leaving group, preferably methylthio or imidazol-1-yl. The reaction is preferably carried out in a suitable solvent, such as ethanol, and at an elevated temperature, most preferably under reflux. Compounds of the formula (XXXX) are readily prepared from a compound of the formula (XX) by methods known to the skilled man.
6. Compounds of the formula (I) in which R2 is xe2x80x94CH2xe2x80x94NR12axe2x80x94Cxe2x95x90N(CN)xe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula (XXXV) with a compound of the formula
R14R13Nxe2x80x94Cxe2x95x90N(CN)xe2x80x94L13xe2x80x83xe2x80x83(XXXXI)
in which L13 is a suitable leaving group, preferably methylthio. The reaction is preferably carried out in a suitable solvent, such as ethanol, and at an elevated temperature, most preferably under reflux. Compounds of the formula (XXXXI) are readily prepared from a compound of the formula (XX) by methods known to the skilled man.
7. Compounds of the formula (I) in which in which R2 is xe2x80x94CH2CH2xe2x80x94NR12axe2x80x94Yxe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula 
with an appropriate reagent and under appropriate conditions in the same way that a compound of the formula (V) may be prepared from a compound of the formula (XVIII). It will be appreciated by the skilled man that in the case where Y is xe2x80x94CSxe2x80x94 or xe2x80x94Cxe2x95x90N(CN)xe2x80x94, the final intermediates will be compounds of the formula (XXXXIII) and (XXXXIV), respectively, in which L14 represents either of L2 or L3 and L15 represents either of L5 or L6. 
Compounds of the formula (XXXXII) may be prepared as shown in Scheme 7, in which P1 and P2 are as defined above. 
In Scheme 7, compounds of the formula (XXXXII) may be prepared by the deprotection of a compound of the formula (XXXXV). Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P1 and P2 are each acetyl, the protecting groups may be removed by treating a solution of the compound of formula (XXXXV) in a suitable solvent, such as a mixture of water and methanol, with a base such as sodium carbonate, typically at room temperature. Compounds of the formula (XXXXV) may be prepared by the reduction of a compound of the formula (XXXXVI) with a suitable reducing agent, preferably a palladium catalyst and hydrogen gas, in the presence of a compound of the formula (XXV). In a typical procedure, where R12a is H, a compound of the formula (XXXXVI) is dissolved in a suitable solvent, such as ethanol, which has been saturated with ammonia gas, a palladium catalyst such as 10% w/w palladium on carbon is added and the reaction mixture is stirred under an atmosphere of hydrogen gas, typically at a pressure of 414 kPa (60 psi). Compounds of the formula (XXXXVI) may be prepared by the reaction of a derivatised form of a compound of the formula (XXXXVII) with a compound of the formula (IV), in which W1 is as defined above. In a typical procedure, the compound of the formula (XXXXVII) is heated with N,O-bis(trimethylacetamide) in an inert solvent such as 1,1,1-trichloroethane, the solvent is removed and a solution of the residue, in a suitable solvent such as toluene, is heated, preferably under reflux, with the compound of the formula (IV) and trimethylsilyltriflate. Compounds of the formula (XXXXVII) may be prepared by the deprotection of a compound of the formula (XXVII), in which P3 is as defined above. Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P3 is tetrahydropyran-2-yl, the protecting group may be removed by treating a solution of the compound of the formula (XXVII) in a suitable solvent, such as ethanol, with an acid such as hydrochloric acid.
8. Compounds of the formula (I) in which R2is xe2x80x94CH2CH2xe2x80x94NR12axe2x80x94COxe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula (XXXXII) with a compound of the formula (XXXVIII) in which L9 and L10 are as defined above to form an intermediate of the formula 
in which L18 represents either of the leaving groups L9 or L10 and the subsequent reaction of this intermediate with a compound of the formula (XX). In a typical example, where L9 and L10 are each imidazol-1-yl, a solution of the compound of the formula (XXXXII) in a suitable solvent, such as dichloromethane, is treated with 1,1xe2x80x2-carbonyldiimidazole. The reaction mixture is stirred, preferably at room temperature, until thin layer chromatography (TLC) indicates that a substantially complete reaction has occurred and then a compound of the formula (XX) is added to give the compound of the formula (I).
9. Compounds of the formula (I) in which R2 is xe2x80x94CH2CH2xe2x80x94NR12axe2x80x94CSxe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula (XXXXII) with a compound of the formula (XXXX) in which L12 is as defined above. The reaction is preferably carried out in a suitable solvent, such as ethanol, and at an elevated temperature, most preferably under reflux.
10. Compounds of the formula (I) in which R2 is xe2x80x94CH2CH2xe2x80x94NR12axe2x80x94Cxe2x95x90N(CN)xe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula (XXXXII) with a compound of the formula (XXXXI) in which L13 is as defined above. The reaction is preferably carried out in a suitable solvent, such as ethanol, and at an elevated temperature, most preferably under reflux.
11. Compounds of the formula (I) in which in which R2 is xe2x80x94CONR10xe2x80x94A1xe2x80x94R11 may be prepared by the reaction of a compound of the formula 
in which E is as defined above, with a compound of the formula (XVII). The reaction is preferably carried out at an elevated temperature, most preferably at from 100 to 150xc2x0 C., and optionally in the presence of a suitable solvent, such as ethanol. In a typical procedure, the compound of the formula (LI) and the compound of the formula (XVII) are heated together at about 120xc2x0 C. Compounds of the formula (LI) may be prepared as shown in Scheme 8, in which P1, P2 and E are as defined above. 
In Scheme 8, compounds of the formula (LI) may be prepared by the deprotection of a compound of the formula (LII). Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P1 and P2 are each acetyl, the protecting groups may be removed by treating a solution of the compound of formula (LII) in a suitable solvent, such as a mixture of water and methanol, with a base such as sodium carbonate, typically at room temperature. Compounds of the formula (LII) may be prepared by the reaction of a derivatised form of a compound of the formula (LIII) with a compound of the formula (IV), in which W1 is as defined above. In a typical procedure, the compound of the formula (LII) is heated with N,O-bis(trimethylacetamide) in an inert solvent such as 1,1,1-trichloroethane, the solvent is removed and a solution of the residue, in a suitable solvent such as toluene, is heated, preferably under reflux, with the compound of the formula (IV) and trimethylsilyltriflate. Compounds of the formula (LIII) may be prepared by the deprotection of a compound of the formula (XV), in which P3 is as defined above. Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P3 is tetrahydropyran-2-yl, the protecting group may be removed by treating a solution of the compound of the formula (XV) in a suitable solvent, such as ethanol, with an acid such as hydrochloric acid.
In certain cases, compounds of the formula (I) in which R2 is xe2x80x94CONR10xe2x80x94A1xe2x80x94R11 may be prepared by the reaction of a compound of the formula (LII) with a compound of the formula (XVII). In such cases, the protecting groups P1 and P2 are removed by the reaction conditions employed. For example, when P1 and P2 are each acetyl, the reaction of a compound of the formula (LII) with a compound of the formula (XVII) at 130xc2x0 C. and in the absence of solvent gives a compound of the formula (I).
12. Compounds of the formula (I) in which R2 is xe2x80x94CONR10xe2x80x94A1xe2x80x94R11 may be prepared by the reaction of a compound of the formula 
in which Z is a suitable leaving group such as bromo, iodo, trialkylstannyl or trifluoromethylsulphonyl, preferably iodo, with a compound of the formula (XVII) in the presence of carbon monoxide and a suitable catalyst. Preferably the catalyst is a palladium (II) catalyst. More preferably, the catalyst is 1,1xe2x80x2-bis(diphenylphosphino)ferrocenedichloropalladium (II) (optionally as a 1:1 complex with dichloromethane). Alternatively, palladium (II) acetate may be used in the presence of a suitable ligand such as 1,1xe2x80x2-bis(diphenylphosphino)ferrocene, triphenylphosphine, tri(o-tolyl)phosphine or (R)xe2x80x94, (S)xe2x80x94 or racemic 2,2xe2x80x2-bis(diphenylphosphino)-1-1xe2x80x2-binaphthyl. In a typical procedure, the reaction is carried out in a sealed vessel in the presence of carbon monoxide (e.g. about 345 kPa, 50 psi) at an elevated temperature (e.g. about 60xc2x0 C.) and in a suitable solvent (e.g. tetrahydrofuran, methanol or ethanol). A suitable organic base such as a tertiary amine (e.g. triethylamine, N-ethyldiisopropylamine or 4-methylmorpholine) may optionally be added.
Compounds of the formula (LIV) may be prepared as shown in Scheme 9, in which P1, P2 and Z are as defined above. 
In Scheme 9, compounds of the formula (LIV) may be prepared by the deprotection of a compound of the formula (LVI). Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P1 and P2 are each acetyl, the protecting groups may be removed by treating a solution of the compound of the formula (LVI) in a suitable solvent, such as a mixture of water and methanol, with a base such as sodium carbonate, typically at room temperature. Compounds of the formula (LVI) may be prepared by the reaction of a compound of the formula (LVII) with a compound of the formula (XIV). Typically, a solution of the compound of the formula (LVII) in a solvent such as isopropyl alcohol is treated with the compound of the formula (XIV) and heated under reflux. An additional acid acceptor such as N,N-diphenylethylamine may optionally be added. In certain cases, the protecting groups P1 and P2 may be removed by these conditions to give a compound of the formula (LIV) directly from a compound of the formula (LVII). Compounds of the formula (LVII) may be prepared by the reaction of a derivatised form of a compound of the formula (LVIII) with a compound of the formula (IV), in which W1 is as defined above. In a typical procedure, the compound of the formula (LVIII) is heated with N,O-bis(trimethylacetamide) in an inert solvent such as 1,1,1-trichloroethane, the solvent is removed and a solution of the residue, in a suitable solvent such as toluene, is heated, preferably under reflux, with the compound of the formula (IV) and trimethylsilyltriflate. Compounds of the formula (LVIII) are either known or easily prepared by methods well known to the skilled man.
13. Compounds of the formula (I) in which R2 is xe2x80x94COxe2x80x94NR18xe2x80x94X1xe2x80x94NR12xe2x80x94Yxe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula 
with an appropriate reagent and under appropriate conditions in the same way that a compound of the formula (V) may be prepared from a compound of the formula (XVIII). It will be appreciated by the skilled man that in the case where Y is xe2x80x94CSxe2x80x94 or xe2x80x94Cxe2x95x90N(CN)xe2x80x94, the final intermediates will be compounds of the formula (LX) and (LXI), respectively, in which L21 represents either of L2 or L3 and L22 represents either of L5 or L6. 
Compounds of the formula (LIX) may be prepared by the reaction of a compound of the formula (LI) with a compound of the formula (XXXI), optionally at an elevated temperature, optionally in an inert solvent (e.g. 1,2-dimethoxyethane or 2-methoxyethyl ether) and optionally under pressure. Preferably, the reaction is carried out in the absence of solvent at a temperature of from 100-120xc2x0 C. The skilled person will appreciate that to achieve the desired regioselectivity, a suitable protecting group (e.g. trifluoroacetyl) may optionally be used for this reaction, located on a chosen N atom of a compound of the formula (XXXI).
14. Compounds of the formula (I) in which R2 is xe2x80x94CONR18xe2x80x94X1xe2x80x94NR12xe2x80x94COxe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula (LIX) with a compound of the formula (XXXVIII) in which L9 and L10 are as defined above to form an intermediate of the formula 
in which L23 represents either of the leaving groups L9 or L10 and the subsequent reaction of this intermediate with a compound of the formula (XX). In a typical example, where L9 and L10 are each imidazol-1-yl, a solution of the compound of the formula (LIX) in a suitable solvent, such as dichloromethane, is treated with 1,1xe2x80x2-carbonyldiimidazole. The reaction mixture is stirred, preferably at room temperature, until thin layer chromatography (TLC) indicates that a substantially complete reaction has occurred and then a compound of the formula (XX) is added to give the compound of the formula (I).
15. Compounds of the formula (I) in which R2 is xe2x80x94CONR18xe2x80x94X1xe2x80x94NR12xe2x80x94CSxe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula (LIX) with a compound of the formula (XXXX) in which L12 is as defined above. The reaction is preferably carried out in a suitable solvent, such as ethanol, and at an elevated temperature, most preferably under reflux.
16. Compounds of the formula (I) in which R2 is xe2x80x94CONR18xe2x80x94X1xe2x80x94NR12xe2x80x94Cxe2x95x90N(CN)xe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula (LIX) with a compound of the formula (XXXXI) in which L13 is as defined above. The reaction is preferably carried out in a suitable solvent, such as ethanol, and at an elevated temperature, most preferably under reflux.
17. Compounds of the formula (I) in which R2 is xe2x80x94CONR18xe2x80x94X1xe2x80x94NR12xe2x80x94Yxe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula (LIV) in which Z is a suitable leaving group such as bromo, iodo, trialkylstannyl or trifluoromethylsulphonyl, preferably iodo, with a compound of the formula
R18NHxe2x80x94X1xe2x80x94NR12xe2x80x94Yxe2x80x94NR13R14xe2x80x83xe2x80x83(LXIII)
in the presence of carbon monoxide and a suitable catalyst. Preferably the catalyst is a palladium (II) catalyst. More preferably, the catalyst is 1,1xe2x80x2-bis(diphenylphosphino)ferrocenedichloropalladium (II) (optionally as a 1:1 complex with dichloromethane). Alternatively, palladium (II) acetate may be used in the presence of a suitable ligand such as 1,1xe2x80x2-bis(diphenylphosphino)ferrocene, triphenylphosphine, tri(o-tolyl)phosphine or (R)xe2x80x94, (S)xe2x80x94 or racemic 2,2xe2x80x2-bis(diphenylphosphino)-1-1xe2x80x2-binaphthyl. In a typical procedure, the reaction is carried out in a sealed vessel in the presence of carbon monoxide at an elevated pressure (e.g. about 345 kPa, 50 psi) at an elevated temperature (e.g. about 60xc2x0 C.) and in a suitable solvent (e.g. tetrahydrofuran, methanol or ethanol). A suitable organic base such as a tertiary amine (e.g. triethylamine, N-ethyldiisopropylamine or 4-methylmorpholine) may optionally be added.
18. Compounds of the formula (I) in which R2 is xe2x80x94CONR18xe2x80x94X1xe2x80x94NR12xe2x80x94Yxe2x80x94NR13R14 may be prepared by the reaction of a compound of the formula (LI) with a compound of the formula (LXIII), optionally at an elevated temperature, optionally in an inert solvent (e.g. 1,2-dimethoxyethane or 2-methoxyethyl ether) and optionally under pressure. Preferably, the reaction is carried out in the absence of solvent at a temperature of from 100-120xc2x0 C.
19. Compounds of the formula (IV) in which R19 is 1,2,4-oxadiazol-5-yl optionally substituted at the 3 position may be prepared as shown in Scheme 10 in which P1 and P2 are as defined above and R22 is H or C1-C6 alkyl, said C1-C6 alkyl being optionally substituted by phenyl, xe2x80x94OH, C1-C6 alkoxy or xe2x80x94NR20R21, R20 and R21 being as defined above. 
In Scheme 10, compounds of the formula (IV) may be prepared by first treating a compound of the formula (LXIV) with an aqueous solution of an acid such as trifluoroacetic acid or hydrochloric acid, optionally at an elevated temperature, and then treating a solution of the intermediate so obtained, in a suitable solvent (e.g. pyridine), with an acylating agent (e.g. acetic anhydride or acetyl chloride when W1 is methyl or benzoyl chloride when W1 is phenyl). Where the protecting groups P1 and P2 in the compound of the formula (LXIV) are removed under acidic conditions, they will be replaced, as a result of this procedure, by new protecting groups P1 and P2 in the compound of the formula (IV) which are either both acetyl or benzoyl. Compounds of the formula (LXIV) may be prepared by heating a solution of a compound of the formula (LXV) in a suitable solvent (e.g. 2-methoxyethyl ether), preferably to 120xc2x0 C. Compounds of the formula (LXV) may be prepared from a compound of the formula (LXVI) by activation of the compound of the formula (LXVI) as, for example, an acid chloride and treatment of this activated intermediate with a compound of the formula
R22C(xe2x95x90NOH)NH2xe2x80x83xe2x80x83(LXVII).
In a typical procedure, a compound of formula (LXVI) is dissolved in a suitable inert solvent (e.g. dichloromethane) and treated with oxalyl chloride and, optionally, a catalytic amount of N,N-dimethylformamide. After removal of excess solvent and reagent by evaporation under reduced pressure, the residue is dissolved in a suitable solvent (e.g. ethyl acetate) and treated with the compound of the formula (LXVII). Compounds of the formula (LXVI) are either known or easily prepared by methods well known in the art.
Compounds of the formula (IV) in which R19 is 1,2,4-triazol-3-yl optionally substituted at the 1 position may be prepared as shown in Scheme 11 in which P1 and P2 are as defined above and R23 is C1-C6 alkyl, said C1-C6 alkyl being optionally substituted by phenyl, xe2x80x94OH, C1-C6 alkoxy or xe2x80x94NR20R21, R20 and R21 being as defined above. 
In Scheme 11, compounds of the formula (IV) may be prepared by first treating a compound of the formula (LXVIII) or a compound of the formula (LXIX) with an aqueous solution of an acid such as trifluoroacetic acid or hydrochloric acid, optionally at an elevated temperature, and then treating a solution of the intermediate so obtained, in a suitable solvent (e.g. pyridine), with an acylating agent (e.g. acetic anhydride or acetyl chloride when W1 is methyl or benzoyl chloride when W1 is phenyl). Where the protecting groups P1 and P2 in the compound of the formula (LXVIII) or (LXIX) are removed under acidic conditions, they will be replaced, as a result of this procedure, by new protecting groups P1 and P2 in the compound of the formula (IV) which are either both acetyl or benzoyl. The skilled man will appreciate that in certain cases, this procedure will derivatise the triazole in a compound of the formula (LXIX) with an acetyl or benzoyl group which will be removed in a subsequent deprotection step. Compounds of the formula (LXVIII) may be prepared by treating a solution of a compound of the formula (LXIX) in a suitable solvent (e.g. acetone) with an alkylating agent of the formula
R23xe2x80x94L24xe2x80x83xe2x80x83(LXXV)
in which L24 is a suitable leaving group such as bromo or iodo, preferably iodo and R23 is as defined above. A base such as potassium carbonate may optionally be added and the reaction is preferably carried out at an elevated temperature, most preferably under reflux. Compounds of the formula (LXIX) may be prepared by the hydrogenation of a compound of the formula (LXX). In a typical procedure, a solution of a compound of the formula (LXX) in a suitable solvent, such as ethyl acetate, ethanol or a mixture thereof, is treated with a suitable catalyst, such as palladium black, and pressurised with hydrogen, preferably to 2758 kPa (400 psi). Compounds of the formula (LXX) may be prepared by treating a solution of a compound of the formula (LXXI) in a suitable solvent, such as acetic acid, with sodium nitrite. Compounds of the formula (LXXI) may be prepared by treating a solution of a compound of the formula (LXXII) in a suitable solvent, such as water, with a base, such as sodium hydroxide, and heating the solution, preferably under reflux. Compounds of the formula (LXXII) may be prepared by treating a solution of a compound of the formula (LXXIII) in a suitable solvent, such as dichloromethane, with benzyl isothiocyanate. Compounds of the formula (LXXIII) may be prepared by the hydrogenation of a compound of the formula (LXXIV). In a typical procedure, a solution of the compound of the formula (LXXIV) in a suitable solvent, such as ethanol, is treated with a suitable catalyst, such as 10% w/w palladium on carbon, and pressurised with hydrogen, preferably to 414 kPa (60 psi). Compounds of the formula (LXXIV) may be prepared from a compound of the formula (LXVI) by activation of the compound of the formula (LXVI) as, for example, an acid chloride and treatment of this activated intermediate with benzyl carbazate. In a typical procedure, the compound of formula (LXVI) is dissolved in a suitable inert solvent (e.g. dichloromethane) and treated with oxalyl chloride and, optionally, a catalytic amount of N,N-dimethylformamide. After removal of excess solvent and reagent by evaporation under reduced pressure, the residue is dissolved in a suitable solvent (e.g. dichloromethane) and treated with benzyl carbazate.
Compounds of the formula (IV) in which R19 is 1,2,4-oxadiazol-3-yl optionally substituted at the 5 position, P1 and P2 are each acetyl and W1 is methyl may be prepared as shown in Scheme 12 in which R22 is as defined above and P1 and P2, in formulas (LXXVII), (LXXVIII) and (LXXIX) are suitable protecting groups as previously defined. 
In Scheme 12, compounds of the formula (IV) may be prepared by the reaction of a compound of the formula (LXXVI) with acetic acid, acetic anhydride and concentrated sulphuric acid. The reaction is carried out in a suitable solvent, such as dichloromethane, and at an elevated temperature, preferably under reflux. Compounds of the formula (LXXVI) may be prepared by the deprotection of a compound of the formula (LXXVII). Suitable conditions for the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P1 and P2, taken together, represent dimethylmethylene, a solution of the compound of the formula (LXXVII) in aqueous hydrochloric acid is stirred at room temperature. Under such acid conditions, epimerisation of the methoxy substituent may occur. Compounds of the formula (LXXVII) may be prepared by the reaction of a compound of the formula (LXXVIII) with a compound of the formula
R22CO2Hxe2x80x83xe2x80x83(LXXX).
In a typical procedure, a solution of the compound of the formula (LXXVIII) and the compound of the formula (LXXX) in a suitable solvent, such as diethylene glycol dimethyl ether, is treated with a suitable acid activating reagent, such as a carbodiimide (preferably 1-(3-dimethylpropyl)-3-ethylcarbodiimide hydrochloride) and heated, preferably at about 110xc2x0 C. Compounds of the formula (LXXVIII) may be prepared by the reaction of a compound of the formula (LXXIX) with hydroxylamine hydrochloride. The reaction is performed in a suitable solvent, such as methanol, preferably under reflux. Compounds of the formula (LXXIX) are either known (see, for example, WO-A-9967265) or are easily prepared by methods well known in the art.
Compounds of the formula (IV) in which R19 is 1,2,3-triazol-4-yl optionally substituted at the 1 position, may be prepared as shown in Scheme 13 in which P1, P2 and R23 are as defined above. 
In Scheme 13, compounds of the formula (IV) may be prepared by first treating a compound of the formula (LXXXI) or a compound of the formula (LXXXII) with an aqueous solution of an acid such as trifluoroacetic acid or hydrochloric acid, optionally at an elevated temperature, and then treating a solution of the intermediate so obtained, in a suitable solvent (e.g. pyridine), with an acylating agent (e.g. acetic anhydride or acetyl chloride when W1 is methyl or benzoyl chloride when W1 is phenyl). Where the protecting groups P1 and P2 in the compound of the formula (LXXXI) or the compound of the formula (LXXXII) are removed under acidic conditions, they will be replaced, as a result of this procedure, by new protecting groups P1 and P2 in the compound of the formula (IV) which are either both acetyl or benzoyl. The skilled man will appreciate that in certain cases, this procedure will derivatise the triazole in a compound of the formula (LXXXII) with an acetyl or benzoyl group which will be removed in a subsequent deprotection step. Compounds of the formula (LXXXI) may be prepared by treating a solution of a compound of the formula (LXXXII) in a suitable solvent (e.g. acetone) with an alkylating agent of the formula (LXXV) in which L24 and R23 are as defined above. A base such as potassium carbonate may optionally be added and the reaction may optionally be carried out at an elevated temperature. Compounds of the formula (LXXXII) may be prepared by the reaction of a compound of the formula (LXXXIII) with trimethylsilylazide. In a typical procedure, a mixture of the compound of the formula (LXXXIII) and trimethylsilylazide are heated together in a teflon lined bomb, preferably at 120xc2x0 C. Compounds of the formula (LXXXIII) are either known (see, for example, Helv. Chim. Acta, 1980, 63, 1181) or are easily prepared by methods well known in the art.
Other compounds of the formula (IV) are either known (see, for example, WO-A-9967265) or are easily prepared by methods well known in the art.
20. Compounds of the formula (I) in which R2 is xe2x80x94Xxe2x80x94NR12axe2x80x94Yxe2x80x94NR13R14 or xe2x80x94COxe2x80x94NR18xe2x80x94X1xe2x80x94NR12xe2x80x94Yxe2x80x94NR13R14 and R14 is xe2x80x94(C2-C6 alkylene)-NR8Ra, wherein Ra is xe2x80x94CONR4R4, xe2x80x94COOR5, xe2x80x94COR5, xe2x80x94SO2R5 or xe2x80x94SO2NR4R4, may be prepared by the derivatisation of an amine of the formula 
or an amine of the formula 
respectively, with a suitable acylating or sulphonylating agent. For example, compounds of the formula (I) in which R2 is xe2x80x94Xxe2x80x94NR12axe2x80x94Yxe2x80x94NR13R14 or xe2x80x94COxe2x80x94NR18xe2x80x94X1xe2x80x94NR12xe2x80x94Yxe2x80x94NR13R14 and R14 is xe2x80x94(C2-C6 alkylene)-NR8COR5 may be prepared by the reaction of a compound of the formula (LXXXIV) or (LXXXV), respectively, with an acid chloride of the formula
R5COClxe2x80x83xe2x80x83(LXXXVI).
In a typical procedure, a solution of the compound of the formula (LXXXIV) or (LXXXV) in a suitable solvent, such as a mixture of ethyl acetate and N-methylpyrrolidinone, is treated with a suitable base, preferably a trialkylamine base such as triethylamine, and the compound of the formula (LXXXVI). As a further example, compounds of the formula (I) in which R2 is xe2x80x94Xxe2x80x94NR12axe2x80x94Yxe2x80x94NR13R14 or xe2x80x94COxe2x80x94NR18xe2x80x94X1xe2x80x94NR12xe2x80x94Yxe2x80x94NR13R14 and R14 is xe2x80x94(C2-C6 alkylene)-NR8SO2R5 may be prepared by the reaction of a compound of the formula (LXXXIV) or (LXXXV) with a compound of the formula
R5SO2Clxe2x80x83xe2x80x83(LXXXVII).
In a typical procedure, a solution of the compound of the formula (LXXXIV) or (LXXXV) in a suitable solvent, such as a mixture of ethyl acetate and N-methylpyrrolidinone, is treated with a suitable base, preferably a trialkylamine base such as triethylamine, and the compound of the formula (LXXXVII).
Compounds of the formula (LXXXIV) and (LXXXV) may be prepared by analogy with the methods presented above for the preparation of compounds of the formula (I). Compounds of the formula (LXXXVI) and (LXXXVII) are either commercially available or are easily prepared by methods well known to the skilled man.
Compounds of the formula (I) may also be interconverted using conventional functional group interconversion techniques.
All of the reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions as well as procedures for isolating the desired products will be well-known to persons skilled in the art with reference to literature precedents and the Examples and Preparations sections below.
A pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
The anti-inflammatory properties of the compounds of the formula (I) are demonstrated by their ability to inhibit neutrophil function which indicates A2a receptor agonist activity. This is evaluated by determining the compound profile in an assay where superoxide production is measured from neutrophils activated by fMLP. Neutrophils were isolated from human peripheral blood using dextran sedimentation followed by centrifugation through Ficoll-Hypaque solution. Any contaminating erythrocytes in the granulocyte pellet were removed by lysis with ice-cold distilled water. Superoxide production from the neutrophils was induced by fMLP in the presence of a priming concentration of cytochalasin B. Adenosine deaminase was included in the assay to remove any endogenously produced adenosine that might suppress superoxide production. The effect of the compound on the fMLP-induced response was monitored colorometrically from the reduction of cytochrome C within the assay buffer. The potency of the compounds was assessed by the concentration giving 50% inhibition (IC50) compared to the control response to fMLP.
The compounds of the formula (I) can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the compounds of the formula (I) can be administered orally, buccally or sublingually in the form of tablets, capsules, multi-particulates, gels, films, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications. The compounds of the formula (I) may also be administered as fast-dispersing or fast-dissolving dosage forms or in the form of a high energy dispersion or as coated particles. Suitable formulations of the compounds of the formula (I) may be in coated or uncoated form, as desired.
Such solid pharmaceutical compositions, for example, tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium stearyl fumarate, sodium lauryl sulphate, stearic acid, glyceryl behenate and talc may be included.
A formulation of the tablet could typically contain between about 0.01 mg and 500 mg of active compound whilst tablet fill weights may range from 50 mg to 1000 mg. An example of a formulation for a 10 mg tablet is illustrated below:
The tablets are manufactured by a standard process, for example, direct compression or a wet or dry granulation process. The tablet cores may be coated with appropriate overcoats.
Solid compositions of a similar type may also be employed as fillers in gelatin or HPMC capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of the formula (I) may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
The compounds of the formula (I) can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion or needleless injection techniques. For such parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, a co-solvent and/or enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage level of the compounds of the formula (I) will usually be from 0.00001 to 100 mg/kg, preferably from 0.0001 to 100 mg/kg (in single or divided doses).
Thus tablets or capsules of the compound of the formula (I) may contain from 0.01 to 500 mg of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
The compounds of formula (I) can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist) or nebuliser, with or without the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide, a further perfluorinated hydrocarbon such as Perflubron (trade mark) or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray, atomiser or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol (optionally aqueous ethanol) or a suitable agent for dispersing, solubilising or extending release and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules, blisters and cartridges (made, for example, from gelatin or HPMC) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the formula (I), a suitable powder base such as lactose or starch and a performance modifier such as L-leucine, manitol or magnesium stearate.
A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 xcexcg to 10 mg of a compound of the formula (I), or a salt thereof, and the actuation volume may vary from 1 to 100 xcexcl. A typical formulation may comprise a compound of the formula (I) or salt thereof, propylene glycol, sterile water, ethanol and sodium chloride.
Aerosol or dry powder formulations are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d contains from 1 to 4000 xcexcg of a compound of the formula (I) for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 1 xcexcg to 20 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
Alternatively, the compounds of the formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. The compounds of the formula (I) may also be dermally or transdermally administered, for example, by the use of a skin patch. They may also be administered by the pulmonary, vaginal or rectal routes.
For application topically to the skin, the compounds of the formula (I) can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds of the formula (I) may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.
Thus the invention provides:
(i) a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof;
(ii) a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof;
(iii) a pharmaceutical composition including a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier;
(iv) a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for use as a medicament;
(v) a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for use as an A2a receptor agonist;
(vi) a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for use as an anti-inflammatory agent;
(vii) a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for use in the treatment of a respiratory disease;
(viii) a compound as in (vii) where the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis;
(ix) a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for use in the treatment of septic shock, male erectile dysfunction, male factor infertility, female factor infertility, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori gastritis, non-Heliobacter pylori gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract or a psychotic disorder, or for wound healing;
(x) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament having A2a receptor agonist activity;
(xi) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of an anti-inflammatory agent;
(xii) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of a respiratory disease;
(xiii) use as in (xii) where the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis;
(xiv) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of septic shock, male erectile dysfunction, male factor infertility, female factor infertility, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori gastritis, non-Heliobacter pylori gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing;
(xv) a method of treatment of a mammal, including a human being, with a A2a receptor agonist including treating said mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof;
(xvi) a method of treatment of a mammal, including a human being, to treat an inflammatory disease including treating said mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof;
(xvii) a method of treatment of a mammal, including a human being, to treat a respiratory disease including treating said mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof;
(xviii) a method as in (xvii) where the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis;
(xix) a method of treatment of a mammal, including a human being, to treat septic shock, male erectile dysfunction, male factor infertility, female factor infertility, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori gastritis, non-Heliobacter pylori gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing, including treating said mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof; and
(xx) certain novel intermediates disclosed herein.
The following Examples illustrate the preparation of the compounds of the formula (I):
1H Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (xcex4) are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCl3, deuterochloroform; DMSO, dimethylsulphoxide. The abbreviation psi means pounds per square inch and LRMS means low resolution mass spectrometry. Where thin layer chromatography (TLC) has been used it refers to silica gel TLC using silica gel 60 F254 plates, Rf is the distance travelled by a compound divided by the distance travelled by the solvent front on a TLC plate.